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Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes

Oncogene volume 38, pages 2192–2205 (2019)Cite this article

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Abstract

Although cell polarity plays an important role in epithelial tumorigenesis, the consequence of polarity protein loss in prostatic tumorigenesis and the underlying mechanisms remain unclear. Using conditional knockout mouse models, we found in the current study that loss of polarity protein Par3 increases prostatic epithelial cell growth, elevates symmetrical cell divisions in basal cells, and randomizes spindle orientation in luminal cells, causing the development of high-grade prostatic intraepithelial neoplasia (PIN). Mechanistically, loss of Par3 dissociates the Par3/merlin/Lats1 complex, consequently inhibiting phosphorylation of Lats1 to attenuate the Hippo pathway. Furthermore, attenuated Hippo pathway enhances nuclear translocation of Yes-associated protein (YAP), which promotes cell proliferation and symmetrical cell divisions through transcriptional activation of Ki-67 and Sox2. In addition, Lats1 dephosphorylation impairs its interaction with G protein signaling modulator 2 (GPSM2, which is also known as LGN) that causes randomization of spindle orientation in luminal cells. Interestingly, co-deletion of Par3 and Lats1 for complete blockade of the Hippo pathway in mice results in prostate tumor initiation, whereas co-deletion of Par3 and YAP for disrupting YAP nuclear translocation reverses the phenotypes to a relatively normal state. Therefore, our findings highlight combination of Par3 loss and blockade of the Hippo pathway as a novel mechanism for prostatic tumorigenesis.

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Acknowledgements

This study was supported by funds from the Ministry of Science and Technology of the People’s Republic of China (2017YFA0102900 to W-QG, 2016YFA0502500 to LZ), National Natural Science Foundation of China (81672543 to Y-XF, 81630073 and 81372189 to W-QG), Science and Technology Commission of Shanghai Municipality (16JC1405700 to W-QG), High Peak IV subject on stem cells and translational medicine from Education Commission of Shanghai Municipality, and KC Wong foundation (to W-QG).

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Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China

    Pei-Jie Zhou, Xiao Wang, Na An, Lianzi Wei, Helen He Zhu, Yu-Xiang Fang & Wei-Qiang Gao

  2. Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, 310058, Hangzhou, Zhejiang, China

    Long Zhang

  3. School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China

    Xingxu Huang

  4. School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, 200030, Shanghai, China

    Wei-Qiang Gao

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  1. Pei-Jie Zhou
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Correspondence to Yu-Xiang Fang or Wei-Qiang Gao.

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Zhou, PJ., Wang, X., An, N. et al. Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes. Oncogene 38, 2192–2205 (2019). https://doi.org/10.1038/s41388-018-0580-x

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